The outcome of viral infection results from interactions between virus and host components. However, the identification of polymorphisms underlying complex viral disease in the human population has proven difficult. Identifying and characterizing polymorphic host genes and pathways which contribute to virus susceptibility and pathology is a critical step for improving our understanding of viral disease as well as for the development of anti-viral therapeutics. Here, we propose to use an experimental animal model to investigate how host polymorphisms influence the response to influenza A virus (lAV) infection. lAV represents an excellent model virus with which to identify host polymorphisms associated with virus induced pathogenesis as host genetic variation contributes to lAV mortality. In addition, lAV infection in the mouse model has been well characterized and recapitulates many aspects of human disease. Therefore, we will 1) use a novel panel of recombinant inbred mouse lines, the Collaborative Cross, to map host polymorphic host loci contributing to the innate immune response to lAV infection, and 2) characterize the innate immune response to lAV infection in the genetically diverse found strains of the Collaborative Cross. PUBLIC HEALTH RELEVANCE: Host genetic polymorphisms influence viral pathogenesis and disease outcome, but have been difficult to identify in human populations. Investigating the role that host polymorphisms play in determining the outcome of influenza A virus infection in an experimental animal model will allow for both the identification of novel genes associated with influenza A virus infection, as well as increasing our understanding of the role that host polymorphisms play in virus-induced pathogenesis.